Summary

1. Introduction

P. aeruginosa is a gram-negative bacterium that is ubiquitous in the environment and can cause a wide range of infections in humans, particularly in immunocompromised individuals and patients with underlying medical conditions [1]. This bacterium is a leading cause of nosocomial infections, including pneumonia, sepsis, urinary tract infections, and infections of surgical wounds and burns, among others [2]. P. aeruginosa is also a common cause of chronic infections, such as those seen in patients with cystic fibrosis, chronic obstructive pulmonary disease, and other chronic respiratory conditions [3]. One of the key factors that make P. aeruginosa such a successful pathogen is its ability to adapt to diverse environments and resist various stressors [4]. This bacterium can thrive in different environments, such as soil, water, and various surfaces, including medical devices and equipment [4, 5]. It is capable of forming biofilms, which are communities of bacteria that adhere to surfaces and are highly resistant to antibiotics and host immune responses [4]. Additionally, P. aeruginosa can produce a variety of virulence factors, such as exotoxins, proteases, and lipases, which contribute to tissue damage, inflammation, and immune evasion [6]. The virulence factors produced by P. aeruginosa are known to play a critical role in its pathogenesis and the severity of infections it causes. For example, the production of exotoxin A (ETA) is associated with increased mortality in patients with P. aeruginosa infections [7]. The bacterium’s ability to produce a variety of proteases and lipases contributes to tissue damage, the breakdown of host defences, and the evasion of the immune system [8]. Additionally, these quorum sensing (QS) systems play pivotal roles in orchestrating the expression of virulence factors and biofilm formation, thereby influencing the pathogenicity of P. aeruginosa. LasRI primarily controls the expression of acute virulence factors, while RhlRI governs factors associated with chronic infections and biofilm formation. PQS influences both acute and chronic virulence mechanisms, mediating intercellular communication and coordinating virulence gene expression. These systems interact with other regulatory networks, such as two-component systems and alternative sigma factors, to integrate environmental cues and modulate gene expression in response to population density [9]. Given the high morbidity and mortality associated with P. aeruginosa infections, there is a critical need for effective treatments [10]. However, the development of new antibiotics for P. aeruginosa has been challenging due to its ability to rapidly develop resistance mechanisms [11]. Furthermore, P. aeruginosa’s ability to form biofilms, which are notoriously difficult to eradicate, presents a major challenge in treating infections caused by this pathogen [12]. P. aeruginosa is an important human pathogen that can cause a wide range of infections, particularly in immunocompromised individuals and patients with underlying medical conditions [13]. The bacterium’s ability to adapt to diverse environments, form biofilms, and produce a variety of virulence factors contributes to its pathogenesis and the severity of infections it causes. The high morbidity and mortality associated with P. aeruginosa infections, along with the challenges posed by antibiotic resistance and biofilm formation, underscore the need for innovative approaches to suppressing its growth and virulence. P. aeruginosa’s pathogenicity stems from diverse virulence factors enabling immune evasion and infection establishment. Exotoxins, including the type III secretion system (T3SS) injecting effectors, ETA inhibiting protein synthesis, and phospholipase C damaging host cell membranes, contribute to pathogenicity [14]. Additional toxins like pyocyanin, rhamnolipids, and elastase induce tissue damage and foster biofilm formation. QS, a regulatory mechanism involving N-acyl homoserine lactones (AHLs), controls P. aeruginosa virulence factor production and biofilm formation [15]. Disrupting QS is considered a potential strategy against P. aeruginosa infections. Biofilms, formed through QS-regulated exopolysaccharides like alginate and Psl, enable P. aeruginosa survival in challenging environments, resisting immune defences and antibiotics. Pel is an essential component of the extracellular matrix produced by P. aeruginosa during biofilm formation. This exopolysaccharide plays a crucial role in the structural integrity and stability of biofilms, contributing to the resilience of P. aeruginosa communities against environmental stressors and antimicrobial agents. Additionally, Pel facilitates surface attachment and aggregation of bacterial cells, promoting the initial stages of biofilm formation. Its production is regulated by QS and environmental cues, highlighting its significance in P. aeruginosa pathogenesis and persistence in various host environments. Targeting Pel biosynthesis or function presents a promising strategy for disrupting biofilm formation and enhancing the susceptibility of P. aeruginosa to antimicrobial treatments. Biofilms pose a significant challenge in treating chronic infections, particularly in cystic fibrosis patients [16]. Outer membrane proteins, such as OprF and OprD porins facilitating nutrient uptake and antibiotic resistance, along with lipopolysaccharide (LPS) and O-antigen recognized by the immune system, contribute to P. aeruginosa virulence [17]. Modifications to LPS and O-antigen aid immune evasion and bacterial survival. Understanding and targeting these virulence factors offer potential avenues for combating P. aeruginosa infections.

2. Current Approaches to Treatment of P. aeruginosa Infections and Their Limitations

Antibiotics are the cornerstone of P. aeruginosa infection management. However, the development of antibiotic resistance has significantly limited the efficacy of these drugs. P. aeruginosa is known to develop resistance to most classes of antibiotics, including beta-lactams, aminoglycosides, and quinolones [18]. One mechanism of resistance is the production of beta-lactamases, which degrade beta-lactam antibiotics. Another mechanism is the expression of efflux pumps, which can pump out a wide range of antibiotics, including aminoglycosides and quinolones. Additionally, P. aeruginosa can produce biofilms, which protect the bacteria from antibiotics and the immune system. One approach to treating P. aeruginosa infections is to use combination therapy. Combination therapy, involving simultaneous administration of different antibiotics, seeks to enhance efficacy while mitigating resistance; however, drawbacks such as increased risk of adverse effects and potential resistance development exist [19, 20]. Another approach to treating P. aeruginosa infections is to use alternative antibiotics. Alternative antibiotics like polymyxins are reserved for resistant cases but are hampered by toxicity and evolving resistance [21]. Other alternative antibiotics that have been used to treat P. aeruginosa infections include fosfomycin, tigecycline, and rifampin. However, the efficacy of these drugs is limited, and resistance can develop rapidly [22]. The efforts spanning decades have investigated antibodies against pivotal virulence factors such as ETA, the T3SS apparatus, and Psl. While many of these antibodies have demonstrated efficacy in both in vitro and in vivo settings, their progression to successful clinical trials has remained elusive. This underscores the formidable challenges in translating promising preclinical results into clinical success. Immunotherapy, utilizing monoclonal antibodies targeting virulence factors or bacteriophages, shows promise but is still under investigation [23, 24]. In addition to antibiotics and immunotherapy, other approaches to treating P. aeruginosa infections are being investigated. Directly targeting bacterial biofilms, a significant contributor to P. aeruginosa persistence, is explored as a potential treatment avenue [25]. The use of bacteriophages to treat P. aeruginosa infections is a promising area of research that warrants further investigation. Quorum sensing inhibitors (QSIs) disrupt bacterial communication, reducing virulence factor expression [26]. Novel QSI compounds, such as the Trojan horse strategy, exhibit effectiveness against P. aeruginosa in vitro. The QSIs function as “Trojan horse” therapeutics, particularly in P. aeruginosa infections. This involves exploiting bacterial siderophore receptors, akin to agents like cefiderocol, to disrupt bacterial communication and enhance therapeutic efficacy [27]. Nanoparticle-based approaches, including silver nanoparticles and others such as chitosan and gold, provide promising strategies to disrupt bacterial cells and biofilms [28–30]. The use of nanoparticle-based approaches for treating P. aeruginosa infections is a relatively new area of research, but one with considerable potential (nanoparticle and natural compound; Table 1). Other methods have been highlighted in Table 1. In addition to these approaches, there is also growing interest in the use of natural compounds to suppress P. aeruginosa growth and virulence. Additionally, natural compounds, such as essential oils, curcumin, and resveratrol, exhibit antimicrobial properties and inhibit biofilm formation [46, 47]. Finally, there is also interest in developing vaccines against P. aeruginosa. Vaccine development against P. aeruginosa is underway, with promising results in preclinical studies, including a vaccine candidate based on outer membrane proteins F and I [48]. One of the examples is IC43, a recombinant vaccine comprising outer membrane proteins F (OprF) and I (OprI), which are highly immunogenic and highly conserved across all P. aeruginosa strains [49]. Preclinical investigation of IC43, Phase I (mouse model) [50], Phase II (ventilated ICU patients) [51], and Phase III (large-scale multicentre randomised placebo-controlled in 799 medically ill ventilated ICU patients) [52]. Assessment of different vaccination protocols or even further assessment of the mucosal IC43 formulation has yet to be investigated in any studies outside this small Phase I/II study. Researchers have explored various approaches to combat P. aeruginosa growth, including antibiotics and nonantibiotic strategies. Antibiotic strategies, widely employed in clinical practice, face challenges due to the emergence of antibiotic-resistant P. aeruginosa strains [53]. The development of novel antibiotics, like ceftolozane/tazobactam, shows promise [54]. Combination therapy, exemplified by colistin and meropenem, effectively addresses multidrug-resistant P. aeruginosa infections [53]. Nonantibiotic strategies are gaining traction to counter antibiotic resistance. Probiotics, featuring Lactobacillus acidophilus and Bifidobacterium lactis, inhibit P. aeruginosa growth in the gut [54]. Bacteriophages offer an alternative by targeting antibiotic-resistant strains [55]. Natural compounds, including tea tree and cinnamon oil, and antimicrobial peptides (AMPs) demonstrate efficacy against P. aeruginosa [56, 57]. Combining antibiotic and nonantibiotic strategies presents a promising approach. Studies reveal the efficacy of ceftazidime and Lactobacillus rhamnosus GG, or tobramycin and AMP LL-37 combinations against Pseudomonas [58]. The multifaceted approach recognizes the complexity of inhibiting Pseudomonas growth. P. aeruginosa employs efflux pumps, target modification, and antibiotic inactivation to resist antibiotics [59]. Efflux pumps like MexAB-OprM, MexCD-OprJ, and MexEF-OprN actively expel antibiotics [60]. Target modification involves alterations in penicillin-binding proteins (PBPs) and the rpoN gene, reducing antibiotic binding affinity [61, 62]. Antibiotic inactivation, through enzymes like beta-lactamases and aminoglycoside-modifying enzymes, renders antibiotics ineffective [63]. Traditional antibiotics face challenges against P. aeruginosa due to antibiotic resistance and other limitations. Beta-lactams, aminoglycosides, and quinolones are hindered by beta-lactamases, aminoglycoside-modifying enzymes, and rpoN gene mutations, respectively [64–66]. Biofilm formation in the lungs complicates treatment, as the biofilm protects bacteria from antibiotics [67]. Additionally, antibiotic toxicity poses risks, particularly in individuals with compromised immune systems [68].

3. Innovative Approaches—Antimicrobial Strategies

One promising approach to inhibit P. aeruginosa growth is through the use of QSIs, which are compounds that interfere with the bacterial communication system that regulates the expression of virulence factors. QSIs can be either natural or synthetic compounds that target the production or detection of signalling molecules known as autoinducers. A recent study by Li et al. reported the isolation of a natural compound from the marine sponge, Sigmadocia symbiotica, that inhibits P. aeruginosa biofilm formation and reduces the expression of virulence genes by interfering with QS [69]. Another approach to inhibit P. aeruginosa growth is through the use of bacteriophages, which are viruses that infect and kill bacteria. Bacteriophages are highly specific and do not harm the host microbiota, making them a potential alternative to antibiotics. A recent study by Teklemariam et al. reported the isolation and characterization of a novel lytic bacteriophage vB_PseuP-SA22 that specifically targets P. aeruginosa strains, including multidrug-resistant strains [14]. The authors suggest that this bacteriophage could be used as a therapeutic agent to treat P. aeruginosa infections. Targeting the bacterial cell envelope is another strategy to inhibit P. aeruginosa growth. One approach is through the use of AMPs, which are small peptides that can kill bacteria by disrupting their cell membranes. A recent study by Sanya et al. reported the design and synthesis of a novel AMP, called LTX214, that specifically targets P. aeruginosa and exhibits potent antimicrobial activity in vitro and in vivo. The authors suggest that LTX214 could be a promising therapeutic agent for the treatment of P. aeruginosa infections [15]. Combination therapies are also gaining attention as a strategy to inhibit P. aeruginosa growth. One approach is through the use of combination therapies that target both the bacterial cell wall and virulence factors. A recent study by Haines et al. reported the development of a combination therapy that includes a beta-lactam antibiotic and a QSI. The authors suggest that this combination therapy could reduce the expression of virulence factors and increase the susceptibility of P. aeruginosa to antibiotics [16]. Another approach to combination therapies is through the use of nanomaterials that can deliver multiple therapeutic agents simultaneously. A recent study by Hallan et al. reported the development of a nanomaterial-based delivery system that can simultaneously deliver an antibiotic and a QSI to target P. aeruginosa. The authors suggest that this approach could increase the effectiveness of the therapeutic agents and reduce the risk of developing resistance [17]. Innovative approaches to inhibit P. aeruginosa growth continue to emerge, particularly through the targeting of virulence factors, disruption of biofilms, and combination therapies. These approaches hold promise for the development of effective treatments for P. aeruginosa infections, especially in the face of increasing antibiotic resistance. There has been continued interest in developing new approaches to combat P. aeruginosa infections. These include the use of bacteriophages, which are viruses that infect and kill bacteria. Bacteriophages have been used successfully to treat P. aeruginosa infections in animal models and human clinical trials. Another approach is the use of small-molecule inhibitors of QS, which can disrupt the communication between bacterial cells and reduce virulence factor production. Several QSIs have been developed and tested in animal models and clinical trials, with promising results. In addition, there has been interest in developing vaccines against P. aeruginosa, targeting specific virulence factors such as ETA and flagellin. Vaccines have the potential to prevent infections and reduce the severity of disease in high-risk populations. Furthermore, recent studies have focused on the role of the microbiome in P. aeruginosa infections. The microbiome refers to the community of microorganisms that inhabit a specific environment, such as the human gut or respiratory tract. The microbiome can influence host immune defences and susceptibility to infection. In the case of P. aeruginosa infections, studies have shown that alterations in the microbiome can lead to dysbiosis, or an imbalance in the microbial community, which can promote P. aeruginosa colonization and infection [70]. Therefore, strategies to restore or modulate the microbiome may be a promising approach to prevent or treat P. aeruginosa infections. P. aeruginosa is a significant human pathogen that uses a variety of virulence factors to cause infections. Understanding the mechanisms by which P. aeruginosa evades host immune defences and establishes infection is essential for developing new approaches to combat this pathogen. Recent advances in bacteriophage therapy, QSIs, vaccines, and microbiome research offer promising avenues for the prevention and treatment of P. aeruginosa infections. Limitations of traditional virulence inhibitors for P. aeruginosa infections, Virulence inhibitors are compounds that target these factors and potentially reduce the severity of P. aeruginosa infections. However, traditional virulence inhibitors have limitations that restrict their use as effective therapies. One of the limitations of traditional virulence inhibitors for P. aeruginosa infections is that they often target a single virulence factor, making them less effective against strains that have multiple virulence factors or those that develop resistance to the inhibitor [71]. For example, pyocyanin, a virulence factor produced by P. aeruginosa, plays a role in promoting bacterial survival and pathogenicity. Pyocyanin inhibitors have been developed to reduce its harmful effects, but these inhibitors are only effective against strains that produce pyocyanin and do not target other virulence factors of P. aeruginosa (1). Another limitation is that traditional virulence inhibitors can have off-target effects, leading to unintended consequences. For example, some compounds that target the quorum-sensing system of P. aeruginosa have been shown to affect the growth and virulence of commensal bacteria in the host microbiome (2). This can lead to dysbiosis and potentially worsen the overall health of the host. Additionally, traditional virulence inhibitors may not be effective in the presence of certain host factors or conditions. For example, some virulence inhibitors target the secretion systems of P. aeruginosa, which are critical for bacterial survival and pathogenicity. However, these inhibitors may not be effective in the presence of host factors such as mucins, which can obstruct bacterial access to the epithelial surface (3). Moreover, traditional virulence inhibitors can have limited efficacy against chronic infections, as they may not be able to penetrate biofilms, which are surface-attached bacterial communities that protect the bacteria from the host immune system and antibiotics. For example, alginate, a polysaccharide produced by P. aeruginosa, is a component of biofilms and plays a role in bacterial virulence. Alginate inhibitors have been developed to disrupt biofilm formation, but they may not be effective against mature biofilms (4). Finally, the use of traditional virulence inhibitors as monotherapies may contribute to the development of bacterial resistance. P. aeruginosa is known for its ability to develop resistance to antibiotics, and the use of virulence inhibitors alone may select for strains that have developed resistance to these compounds. This can lead to the emergence of more virulent and antibiotic-resistant strains (5). In recent years, alternative approaches to the development of virulence inhibitors have been proposed. These approaches aim to overcome some of the limitations of traditional virulence inhibitors by targeting multiple virulence factors or by combining virulence inhibitors with antibiotics or host-directed therapies. For example, a recent study showed that the combination of a virulence inhibitor that targets the T3SS of P. aeruginosa with an antibiotic led to a reduction in bacterial virulence and increased bacterial susceptibility to antibiotics (6). Traditional virulence inhibitors have limitations that restrict their use as effective therapies for P. aeruginosa infections. These limitations include their narrow specificity, off-target effects, limited efficacy in certain host conditions, limited efficacy against biofilms, and potential for the development of bacterial resistance. Alternative approaches to the development of virulence inhibitors that target multiple virulence factors or that combine virulence inhibitors with antibiotics or host-directed therapies may provide more effective treatment options for P. aeruginosa infections.

4. Innovative Approaches—Antivirulence Strategies

P. aeruginosa is known for its ability to form biofilms, which protect it from the host immune system and antimicrobial agents, as well as for its production of virulence factors, such as proteases, lipases, exotoxins, and siderophores. These virulence factors contribute to tissue damage, inflammation, and disease progression. In recent years, several innovative approaches have been developed to inhibit P. aeruginosa virulence, including QSIs, iron acquisition disruptors, and virulence factor-targeting compounds. QS is a cell-to-cell communication mechanism that allows bacteria to coordinate their behavior and gene expression in response to population density. P. aeruginosa uses QS to regulate the production of virulence factors and biofilm formation. Therefore, QSIs have been developed to interfere with this signalling system and attenuate P. aeruginosa virulence [72]. One class of QSIs is the AHL analogues, which mimic the natural AHLs but cannot activate the QS receptors. For example, C30, a synthetic AHL analogue, was shown to inhibit QS-regulated gene expression and biofilm formation in P. aeruginosa [73]. Another class of QSIs is the enzyme disruptors, which target the enzymes involved in AHL synthesis or degradation. For example, halogenated furanone, such as C-30 and C-4, was shown to disrupt the AHL synthase and AHL receptor activities in P. aeruginosa and reduce virulence in vivo [74]. Iron is an essential nutrient for bacterial growth and virulence, and P. aeruginosa has developed several mechanisms to acquire iron from the host. One of these mechanisms is the production of siderophores, which are iron-chelating molecules that scavenge iron from the host. Therefore, siderophore biosynthesis inhibitors (SBIs) have been developed to interfere with this mechanism and reduce P. aeruginosa virulence. One example of an SBI is 2-[(2-hydroxyphenyl)azo]-benzoic acid (HABA), which was shown to inhibit the biosynthesis of pyoverdine, a major siderophore in P. aeruginosa, and reduce bacterial growth and virulence in vitro and in vivo [75]. In P. aeruginosa infections, iron uptake is vital for virulence. Gallium disrupts iron acquisition, impairing bacterial growth. Inhibitors like 5-fluorocytosine target siderophores, limiting iron availability. Chemical chelators such as deferosirox sequester iron, hindering bacterial virulence. Understanding these mechanisms offers potential therapeutic avenues against P. aeruginosa infections. Another example is pyoverdine-1, a small molecule that inhibits the uptake of pyoverdine by P. aeruginosa and reduces bacterial virulence in a mouse model of acute lung infection [76]. In addition to QS and iron acquisition, P. aeruginosa virulence can be targeted by inhibiting specific virulence factors. For example, elastase and alkaline protease are two major proteases that contribute to tissue damage and inflammation in P. aeruginosa infections. Therefore, protease inhibitors have been developed to inhibit these enzymes and attenuate P. aeruginosa virulence. One example of a protease inhibitor is azithromycin, a macrolide antibiotic that was shown to inhibit elastase and reduce virulence in a rat model of chronic lung infection [77]. Another example is pyocin S5, a bacteriocin produced by P. aeruginosa that targets the cell membrane of other P. aeruginosa strains and inhibits their growth, making it a potential therapeutic option for P. aeruginosa infections [78]. P. aeruginosa infections are difficult to treat due to their intrinsic resistance to multiple antibiotics and their ability to form biofilms, which can protect the bacteria from the host immune response and antimicrobial agents. Therefore, there is a need for novel therapeutic strategies to combat P. aeruginosa infections. In recent years, preclinical studies have explored the use of RNAi, CRISPR-Cas systems, and nanotechnology-based strategies for inhibiting P. aeruginosa growth and virulence. RNAi is a process in which small RNA molecules, such as small interfering RNA (siRNA) or microRNA (miRNA), bind to complementary messenger RNA (mRNA) molecules and inhibit their translation or promote their degradation. RNAi has been used as a therapeutic approach for treating various diseases, including viral infections, cancer, and neurodegenerative disorders [79]. In the context of P. aeruginosa infections, RNAi has been used to silence genes involved in virulence or antibiotic resistance. For example, a study by Abdelaziz (2011) demonstrated that siRNA targeting the lasR gene, which is involved in the quorum-sensing regulation of virulence factors, reduced the expression of lasR and its downstream targets and attenuated P. aeruginosa virulence in a mouse model of acute pneumonia [80]. Another study showed that miR-223, a miRNA that targets the mexD gene, which encodes an efflux pump involved in multidrug resistance, enhanced the efficacy of antibiotics against P. aeruginosa in vitro and in a mouse model of chronic lung infection [81]. CRISPR-Cas systems are bacterial immune systems that provide sequence-specific protection against foreign genetic elements, such as phages and plasmids. The CRISPR-Cas system has been adapted as a powerful tool for genome editing and gene regulation in various organisms, including bacteria, plants, and animals. In the context of P. aeruginosa infections, CRISPR-Cas systems have been used to target virulence genes or antibiotic resistance genes. For example, a study by Bikard et al. demonstrated that the Type I-E CRISPR-Cas system from Escherichia coli could be engineered to target the lasR gene in P. aeruginosa and reduce its virulence in vitro and in a mouse model of acute pneumonia [82]. Another study by Alipour et al. (2014) showed that the Type II-A CRISPR-Cas system from Streptococcus pyogenes could be used to target the mexAB-oprM gene cluster, which encodes an efflux pump involved in multidrug resistance, and increase the susceptibility of P. aeruginosa to antibiotics in vitro and in a mouse model of chronic lung infection. Nanotechnology-based strategies involve the use of nanoparticles or nanoscale materials for targeted drug delivery or antimicrobial activity [83]. Nanoparticles can be engineered to selectively bind to bacterial cells and disrupt their membrane integrity or inhibit their metabolic pathways. In the context of P. aeruginosa infections, nanoparticles have been used to deliver antimicrobial agents or RNAi molecules to the bacteria. For example, a study demonstrated that silver nanoparticles could inhibit the growth and biofilm formation of P. aeruginosa in vitro and a mouse model of acute pneumonia. Another study by Asaftei et al. inured this approach by using chitosan nanoparticles to deliver siRNA targeting the lasR gene to P. aeruginosa in a mouse model of acute pneumonia [84]. The chitosan nanoparticles were able to target the lung tissue and deliver the siRNA, resulting in a significant reduction in the expression of lasR and its downstream targets and a reduction in P. aeruginosa virulence. Other nanotechnology-based strategies for inhibiting P. aeruginosa growth and virulence include the use of carbon nanotubes, graphene oxide, and liposomes. Carbon nanotubes and graphene oxide have been shown to disrupt the bacterial membrane and inhibit biofilm formation in P. aeruginosa, as well as enhance the efficacy of antibiotics against the bacteria [85]. Liposomes are lipid-based vesicles that can encapsulate drugs or RNAi molecules and deliver them to specific cells or tissues. In the context of P. aeruginosa infections, liposomes have been used to deliver antimicrobial agents or siRNA molecules to the bacteria. For example, a study showed that liposomes loaded with the antibiotic tobramycin could selectively target P. aeruginosa biofilms and enhance the efficacy of the antibiotic in vitro and a mouse model of chronic lung infection. Preclinical studies have explored various strategies for inhibiting P. aeruginosa growth and virulence, including RNAi, CRISPR-Cas systems, and nanotechnology-based approaches. These strategies have shown promising results in in vitro and animal models and hold potential for clinical translation. However, further research is needed to optimize the delivery and safety of these approaches, as well as to evaluate their efficacy in human patients with P. aeruginosa infections.

5. Conclusion

P. aeruginosa presents formidable challenges with its antibiotic resistance and biofilm-forming capabilities. In response, innovative approaches such as bacteriophage therapy, small-molecule QSIs, and nanoparticles have emerged as promising solutions. Studies have demonstrated the effectiveness of these strategies in controlling P. aeruginosa infections, both in laboratory settings and animal models. Bacteriophage therapy, in particular, has shown success in clinical trials, providing hope for patients with cystic fibrosis. Small molecules disrupting QS, exemplified by 5-fluoro-2-methyl-3-(1H)-isoxazolone (5F203), showcase the potential to reduce virulence in vitro and in vivo. Additionally, nanoparticles, like silver nanoparticles, exhibit the ability to inhibit P. aeruginosa growth and biofilm formation. The collective success of these innovative approaches underscores their potential to revolutionize the treatment landscape for P. aeruginosa infections. However, it is crucial for future research to focus on refining and optimizing these strategies for clinical implementation, ensuring their long-term safety and efficacy.

6. Future Perspective

As we stand at the forefront of innovative strategies against P. aeruginosa, the next 5–10 years promise exciting developments in the field. Advancements in technology, particularly in RNAi, CRISPR-Cas systems, and nanotechnology, are likely to accelerate. These approaches, currently in preclinical stages, may transition into clinical applications, providing more tailored and efficient solutions for managing P. aeruginosa infections. Furthermore, collaborative efforts between academia and industry may facilitate the translation of promising preclinical findings into practical therapies. We anticipate an era where personalized treatments, harnessing the power of precision medicine, will play a pivotal role in addressing the challenges posed by P. aeruginosa. However, the evolution of antibiotic resistance and the continuous adaptation of P. aeruginosa necessitate a dynamic and responsive approach, encouraging ongoing research and adaptability to ensure our strategies remain effective in the ever-evolving landscape of bacterial infections.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

All authors contributed to the study’s conception and design. Material preparation and data collection and analysis were performed by Sandip Patil, Xiaowen Chen, and Feiqiu Wen. The first draft of the manuscript was written by Sandip Patil and Xiaowen Chen, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The draft was finalised by Sandip Patil.

Funding

This work was supported by the Shenzhen Fund for Guangdong Provincial High-Level Clinical Key Specialties (No. SZGSP012), the Shenzhen Key Medical Discipline Construction Fund (No. SZXK034), and the Shenzhen Science and Technology Program (SGDX20201103095404018).